Bone marrow (BM) mesenchymal stem cells (MSCs) are critical components of the BM microenvironment and play an essential role in supporting hematopoiesis. Dysfunction of MSCs is associated with the impaired BM microenvironment that promotes leukemia development. However, whether and how restoration of the impaired BM microenvironment can inhibit leukemia development remain unknown. Using an established leukemia model and the RNA-Seq analysis, we discovered functional degeneration of MSCs during leukemia progression. Importantly, intra-BM instead of systemic transfusion of donor healthy MSCs restored the BM microenvironment, demonstrated by functional recovery of host MSCs, improvement of thrombopoiesis, and rebalance of myelopoiesis. Consequently, intra-BM MSC treatment reduced tumor burden and prolonged survival of the leukemia-bearing mice. Mechanistically, donor MSC treatment restored the function of host MSCs and reprogrammed host macrophages into arginase 1 positive phenotype with tissue-repair features. Transfusion of MSC-reprogrammed macrophages largely recapitulated the therapeutic effects of MSCs. Taken together, our study reveals that donor MSCs reprogram host macrophages to restore the BM microenvironment and inhibit leukemia development.
Subscribe to Journal
Get full journal access for 1 year
only $33.25 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Ren G, Zhang L, Zhao X, Xu G, Zhang Y, Roberts AI, et al. Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell. 2008;2:141–50.
Prockop DJ. Inflammation, fibrosis, and modulation of the process by mesenchymal stem/stromal cells. Matrix Biol. 2016;51:7–13.
Shi Y, Wang Y, Li Q, Liu K, Hou J, Shao C, et al. Immunoregulatory mechanisms of mesenchymal stem and stromal cells in inflammatory diseases. Nat Rev Nephrol. 2018;14:493–507.
Le Blanc K, Mougiakakos D. Multipotent mesenchymal stromal cells and the innate immune system. Nat Rev Immunol. 2012;12:383–96.
Mittal M, Tiruppathi C, Nepal S, Zhao YY, Grzych D, Soni D, et al. TNFalpha-stimulated gene-6 (TSG6) activates macrophage phenotype transition to prevent inflammatory lung injury. Proc Natl Acad Sci USA. 2016;113:E8151–8.
Wang G, Cao K, Liu K, Xue Y, Roberts AI, Li F, et al. Kynurenic acid, an IDO metabolite, controls TSG-6-mediated immunosuppression of human mesenchymal stem cells. Cell Death Differ. 2018;25:1209–23.
Du L, Lin L, Li Q, Liu K, Huang Y, Wang X, et al. IGF-2 preprograms maturing macrophages to acquire oxidative phosphorylation-dependent anti-inflammatory properties. Cell Metab. 2019;29:1363–.e8.
Eggenhofer E, Benseler V, Kroemer A, Popp FC, Geissler EK, Schlitt HJ, et al. Mesenchymal stem cells are short-lived and do not migrate beyond the lungs after intravenous infusion. Front Immunol. 2012;3:297.
Ehninger A, Trumpp A. The bone marrow stem cell niche grows up: mesenchymal stem cells and macrophages move. J Exp Med. 2011;208:421–8.
Chen J, Yao Y, Gong C, Yu F, Su S, Chen J, et al. CCL18 from tumor-associated macrophages promotes breast cancer metastasis via PITPNM3. Cancer Cell. 2011;19:541–55.
Gubin MM, Esaulova E, Ward JP, Malkova ON, Runci D, Wong P, et al. High-dimensional analysis delineates myeloid and lymphoid compartment remodeling during successful immune-checkpoint cancer therapy. Cell. 2018;175:1014–30. e1019.
Chen CC, Wang L, Plikus MV, Jiang TX, Murray PJ, Ramos R, et al. Organ-level quorum sensing directs regeneration in hair stem cell populations. Cell. 2015;161:277–90.
Liu C, Wu C, Yang Q, Gao J, Li L, Yang D, et al. Macrophages mediate the repair of brain vascular rupture through direct physical adhesion and mechanical traction. Immunity. 2016;44:1162–76.
Winkler IG, Sims NA, Pettit AR, Barbier V, Nowlan B, Helwani F, et al. Bone marrow macrophages maintain hematopoietic stem cell (HSC) niches and their depletion mobilizes HSCs. Blood. 2010;116:4815–28.
Bosurgi L, Cao YG, Cabeza-Cabrerizo M, Tucci A, Hughes LD, Kong Y, et al. Macrophage function in tissue repair and remodeling requires IL-4 or IL-13 with apoptotic cells. Science. 2017;356:1072–6.
Cho DI, Kim MR, Jeong HY, Jeong HC, Jeong MH, Yoon SH, et al. Mesenchymal stem cells reciprocally regulate the M1/M2 balance in mouse bone marrow-derived macrophages. Exp Mol Med. 2014;46:e70.
Nemeth K, Leelahavanichkul A, Yuen PS, Mayer B, Parmelee A, Doi K, et al. Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat Med. 2009;15:42–9.
Wang J, Liu Y, Li Z, Du J, Ryu MJ, Taylor PR, et al. Endogenous oncogenic Nras mutation promotes aberrant GM-CSF signaling in granulocytic/monocytic precursors in a murine model of chronic myelomonocytic leukemia. Blood. 2010;116:5991–6002.
Wang J, Liu Y, Li Z, Wang Z, Tan LX, Ryu MJ, et al. Endogenous oncogenic Nras mutation initiates hematopoietic malignancies in a dose- and cell type-dependent manner. Blood. 2011;118:368–79.
Wang JY, Kong GY, Liu YG, Du J, Chang YI, Tey SR, et al. Nras(G12D/+) promotes leukemogenesis by aberrantly regulating hematopoietic stem cell functions. Blood. 2013;121:5203–7.
Li Q, Haigis KM, McDaniel A, Harding-Theobald E, Kogan SC, Akagi K, et al. Hematopoiesis and leukemogenesis in mice expressing oncogenic NrasG12D from the endogenous locus. Blood. 2011;117:2022–32.
Lim M, Pang Y, Ma S, Hao S, Shi H, Zheng Y, et al. Altered mesenchymal niche cells impede generation of normal hematopoietic progenitor cells in leukemic bone marrow. Leukemia. 2016;30:154–62.
Zhu H, Guo ZK, Jiang XX, Li H, Wang XY, Yao HY, et al. A protocol for isolation and culture of mesenchymal stem cells from mouse compact bone. Nat Protoc. 2010;5:550–60.
Rombouts WJ, Ploemacher RE. Primary murine MSC show highly efficient homing to the bone marrow but lose homing ability following culture. Leukemia. 2003;17:160–70.
Medina RJ, O’Neill CL, O’Doherty TM, Knott H, Guduric-Fuchs J, Gardiner TA, et al. Myeloid angiogenic cells act as alternative M2 macrophages and modulate angiogenesis through interleukin-8. Mol Med. 2011;17:1045–55.
Ohnishi H, Kobayashi H, Okazawa H, Ohe Y, Tomizawa K, Sato R, et al. Ectodomain shedding of SHPS-1 and its role in regulation of cell migration. J Biol Chem. 2004;279:27878–87.
Wynn TA, Vannella KM. Macrophages in tissue repair, regeneration, and fibrosis. Immunity. 2016;44:450–62.
Liu C, Wu CA, Yang QF, Gao J, Li L, Yang DQ, et al. Macrophages mediate the repair of brain vascular rupture through direct physical adhesion and mechanical traction. Immunity. 2016;44:1162–76.
Schenk S, Mal N, Finan A, Zhang M, Kiedrowski M, Popovic Z, et al. Monocyte chemotactic protein-3 is a myocardial mesenchymal stem cell homing factor. Stem Cells. 2007;25:245–51.
Kato T, Khanh VC, Sato K, Takeuchi K, Carolina E, Yamashita T, et al. SDF-1 improves wound healing ability of glucocorticoid-treated adipose tissue-derived mesenchymal stem cells. Biochem Biophys Res Commun. 2017;493:1010–7.
Bruno S, Grange C, Deregibus MC, Calogero RA, Saviozzi S, Collino F, et al. Mesenchymal stem cell-derived microvesicles protect against acute tubular injury. J Am Soc Nephrol. 2009;20:1053–67.
Zhou Y, Xu H, Xu W, Wang B, Wu H, Tao Y, et al. Exosomes released by human umbilical cord mesenchymal stem cells protect against cisplatin-induced renal oxidative stress and apoptosis in vivo and in vitro. Stem Cell Res Ther. 2013;4:34.
Hanoun M, Zhang D, Mizoguchi T, Pinho S, Pierce H, Kunisaki Y, et al. Acute myelogenous leukemia-induced sympathetic neuropathy promotes malignancy in an altered hematopoietic stem cell niche. Cell Stem Cell. 2014;15:365–75.
This work was supported by grants from the National Key R&D Program of China (2019YFA0110200), the Strategic Priority Research Program of Chinese Academy of Sciences (XDA16010601), the Chinese Ministry of Science and Technology (2015CB964401, 2016YFA0100601, 2016YFA0100600, 2017YFA0103401, and 2015CB964902), the Major Research and Development Project of Guangzhou Regenerative Medicine and Health Guangdong Laboratory (2018GZR110104006 and 2018GZR0201008), the CAS Key Research Program of Frontier Sciences (QYZDB-SSW-SMC057), the Health and Medical Care Collaborative Innovation Program of Guangzhou Scientific and Technology (201803040017), CAMS Innovation Fund for Medical Sciences (2016-12M-1-002), the General Program from Guangzhou Scientific and Technological Project (201707010157), the Science and Technology Planning Project of Guangdong Province (2017B030314056 and 2017B020230004), the grants from the National Natural Science Foundation of China (Grant nos. 81925002, 81970099, 31471117, 31271457, 81470281, 81421002, 81730006, 31600948, and 81861148029), the CAMS Initiative for Innovative Medicine (2016-I2M-1-017), and the grants from NIH, USA (AI079087, DW and HL130724, DW).
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Xia, C., Wang, T., Cheng, H. et al. Mesenchymal stem cells suppress leukemia via macrophage-mediated functional restoration of bone marrow microenvironment. Leukemia 34, 2375–2383 (2020). https://doi.org/10.1038/s41375-020-0775-3
Blood Science (2021)
Journal of Molecular Cell Biology (2021)
Frontiers in Cell and Developmental Biology (2021)
Tumor Microenvironment Uses a Reversible Reprogramming of Mesenchymal Stromal Cells to Mediate Pro-tumorigenic Effects
Frontiers in Cell and Developmental Biology (2020)
Conditioned Medium From Azurin-Expressing Human Mesenchymal Stromal Cells Demonstrates Antitumor Activity Against Breast and Lung Cancer Cell Lines
Frontiers in Cell and Developmental Biology (2020)